TCDD and its structural analogs such as the polychlorinated dibenzofurans (PCDFs) appear to exert their effects through a mechanism requiring the Ah receptor. TCDD is a potent hepatocarcinogen in female rats but not male rats. Our studies focused on potential mechanisms for the observed sex specificity in a two-stage model for hepatocarcinogenesis in female rats using diethylnitrosamine (DEN) as the initiating agent and TCDD as the promoting agent. These studies revealed that ovarian hormones were required for the tumor promoting actions of TCDD in rat liver. In contrast, ovarian hormones prevented the tumor promoting actions of TCDD in lung. Dos-response relationships for TCDD effects on a number of parameters have been evaluated including CYP1A1 and 1A2 induction, epidermal growth factor receptor, estrogen receptor, cell proliferation, preneoplastic lesions, clinical chemistries, TCDD tissue concentrations, other dioxin responsive genes and possible oncogene activation. These studies have revealed that dose response relationships are different for different parameters. For example, CYP1A1 and 1A2 induction occurs at much lower doses (0.1-0.3 ng/kg/day) than effects on cell proliferation or preneoplastic lesions. Mathematical analyses of our dose response data for TCDD's effects on CYP1A1, CYP1A2 and EGF receptor indicated that the best fit to the data was a linear relationship between liver TCDD concentration and response. Similar conclusions were reached when a mechanistic model for TCDD's effects was used to predict dose response relationships. Dose- response relationships were also evaluated by immunocytochemistry and these studies demonstrated that liver cells were heterogeneous in their response to TCDD. Other studies are comparing rodent and human responses by two approaches (1) in vitro culture of human and rodent lymphocytes with TCDD and (2) comparing rodent responses to human effects in cases where humans have been accidentally exposed to TCDD and/or its structural analogs. These studies indicate that human responses to TCDD are similar to those of rats. Of particular interest was our findings of inter- individual variation in concentrations of human Ah receptor.